Pleiotropic Mechanisms Indicated for Sex Differences in Autism
Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment...
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| creator | Mitra, Ileena Tsang, Kathryn Ladd-Acosta, Christine Croen, Lisa A Aldinger, Kimberly A Hendren, Robert L Traglia, Michela Lavillaureix, Alinoë Zaitlen, Noah Oldham, Michael C Levitt, Pat Nelson, Stanley Amaral, David G Hertz-Picciotto, Irva Fallin, M Daniele Weiss, Lauren A |
| description | Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms. |
| doi_str_mv | 10.1371/journal.pgen.1006425 |
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Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1006425</identifier><identifier>PMID: 27846226</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Autism ; Autism Spectrum Disorder - genetics ; Autism Spectrum Disorder - pathology ; Biology and Life Sciences ; Brain - growth & development ; Brain - pathology ; Brain research ; Child Development Disorders, Pervasive - genetics ; Child Development Disorders, Pervasive - pathology ; Chromosomes ; Chromosomes, Human, X - genetics ; Datasets ; Female ; Funding ; Gender differences ; Gene-Environment Interaction ; Genes ; Genetic Predisposition to Disease ; Genetics ; Genome-Wide Association Study ; Genomes ; Genotype ; Health aspects ; Humans ; Male ; Males ; Medicine ; Medicine and Health Sciences ; Physical Sciences ; Physiological aspects ; Polymorphism, Single Nucleotide - genetics ; Psychiatry ; Public health ; Sex Characteristics ; Sex differences (Psychology) ; Social Sciences</subject><ispartof>PLoS genetics, 2016-11, Vol.12 (11), p.e1006425-e1006425</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Mitra I, Tsang K, Ladd-Acosta C, Croen LA, Aldinger KA, Hendren RL, et al. (2016) Pleiotropic Mechanisms Indicated for Sex Differences in Autism. PLoS Genet 12(11): e1006425. doi:10.1371/journal.pgen.1006425</rights><rights>2016 Mitra et al 2016 Mitra et al</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Mitra I, Tsang K, Ladd-Acosta C, Croen LA, Aldinger KA, Hendren RL, et al. (2016) Pleiotropic Mechanisms Indicated for Sex Differences in Autism. 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Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. 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| subjects | Autism Autism Spectrum Disorder - genetics Autism Spectrum Disorder - pathology Biology and Life Sciences Brain - growth & development Brain - pathology Brain research Child Development Disorders, Pervasive - genetics Child Development Disorders, Pervasive - pathology Chromosomes Chromosomes, Human, X - genetics Datasets Female Funding Gender differences Gene-Environment Interaction Genes Genetic Predisposition to Disease Genetics Genome-Wide Association Study Genomes Genotype Health aspects Humans Male Males Medicine Medicine and Health Sciences Physical Sciences Physiological aspects Polymorphism, Single Nucleotide - genetics Psychiatry Public health Sex Characteristics Sex differences (Psychology) Social Sciences |
| title | Pleiotropic Mechanisms Indicated for Sex Differences in Autism |
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